(−)-Huperzine A (1) is a tricyclic alkaloid produced by the Chinese herb Huperzia serrata.1 (−)-Huperzine A (1) is a potent, selective, and reversible inhibitor of acetylcholine esterase (AChE, Ki=23 nM).2 Recent studies have established that this activity may be exploited to counteract organophosphate chemical warfare agents, such as sarin and VX, by inhibiting their covalent modification of peripheral and cerebral AChE.3 A large body of evidence also suggests that (−)-huperzine A (1) may slow the progression of neurodegenerative diseases, including Alzheimer's disease.4 (−)-Huperzine A (1) is well tolerated in humans, even at doses well above those required clinically.5 Consequently, clinical investigation of (−)-huperzine A (1) is a subject of intense research in the pharmaceutical and defense industries.
The primary obstacle to the clinical development of (−)-huperzine A (1) has been one of supply. Extraction from natural sources is low-yielding (average yield=0.011% from the dried herb),4a and overharvesting has caused a rapid decline in the abundance of Huperziaceae.6 Compounding these issues, the producing species requires nearly 20 years to reach maturity.6 
Total synthesis offers an alternative potential source of huperzine. An enantioselective synthesis is highly desirable, because (+)-huperzine A is significantly less potent than the natural (−)-antipode (1).7 The first total syntheses of (±)-huperzine A were reported by Kozikowski and Xia8 and Qian and Ji.9 A chiral auxiliary-based route was later developed by Kozikowski et al.10 In the interceding years, several research groups have reported modifications to the Kozikowski route,11 as well as complete,12 partial,13 and formal14 routes to huperzine. Nonetheless, Kozikowski's chiral controller-based route,10 which proceeds in 16 steps and ca. 2.8% yield, remains the most efficient published pathway to synthetic (−)-huperzine A (1).15 
Given the large number of steps and relatively poor stereochemical yield of known processes for making (−)-huperzine A, and the increasing importance of (−)-huperzine A as a neuroprotective agent, the need exists for improved methods of making substantially pure (−)-huperzine A in yields that facilitate scale-up to commercial manufacturing.